Nucleic acid nanostructures with core motifs

Abstract

Optimized inhibitory nucleic acids are provided. The nucleic acids have sequences which include an optimal inhibitory motif, such as a GGG. Related methods are also described.

We claim: 
     
       1. A spherical nucleic acid (SNA) comprising, a dense configuration of oligonucleotides radially positioned around a core, wherein the oligonucleotides have a length of 8-200 nucleotides and include at least one GGG, wherein the oligonucleotides are antisense oligonucleotides, wherein the oligonucleotides comprise the following structure:
   5′ X 1 GGGX 2  3′
 
 wherein X 1  and X 2  are, independent of one another, any nucleotide; 
 wherein the core is a liposomal core that comprises a lipid bilayer, 
 wherein the oligonucleotides are single-stranded, 
 wherein the oligonucleotides are indirectly linked to the core through a linker, 
 wherein the oligonucleotides have an mRNA target, and wherein the mRNA target is interleukin-17 receptor A1 (IL17RA). 
 
     
     
       2. The SNA of  claim 1 , wherein X 1  is selected from the group consisting of G and A. 
     
     
       3. The SNA of  claim 1 , wherein 5′ X 1 GGGX 2  3′ is selected from the group consisting of GGGG, GGGT, AGGG and GGGC. 
     
     
       4. The SNA of  claim 1 , wherein the oligonucleotides include 2-5 GGG motifs. 
     
     
       5. The SNA of  claim 1 , wherein the liposomal core is comprised of one type of lipid. 
     
     
       6. The SNA of  claim 1 , wherein the liposomal core is comprised of 2-10 different lipids. 
     
     
       7. The SNA of  claim 1 , wherein the oligonucleotides are nucleolipids. 
     
     
       8. The SNA of  claim 1 , wherein the at least one GGG is positioned at the 5′ end of the oligonucleotide within the first 10 nucleotides. 
     
     
       9. The SNA of  claim 1 , wherein the at least one GGG is positioned at the 3′ end of the oligonucleotide within the 10 nucleotides at the 3′ end. 
     
     
       10. The SNA of  claim 1 , wherein the at least one GGG is positioned in the center of the oligonucleotide. 
     
     
       11. The SNA of  claim 1 , wherein the oligonucleotides comprise a hexaethylene glycol. 
     
     
       12. The SNA of  claim 1 , wherein at least 25 to 200 oligonucleotides are on the exterior of the lipidated structure. 
     
     
       13. The SNA of  claim 1 , wherein at least 50 to 100 oligonucleotides are on the exterior of the lipidated structure. 
     
     
       14. The SNA of  claim 5 , wherein the lipid is dioleoylphosphatidylcholine (DOPC). 
     
     
       15. The SNA of  claim 1 , wherein the core is a hollow core. 
     
     
       16. The SNA of  claim 1 , wherein the linker comprises a cholesterol. 
     
     
       17. The SNA of  claim 1 , wherein the oligonucleotides are conjugated to the linker via the 3′-end. 
     
     
       18. The SNA of  claim 1 , wherein the linker comprises two hexatheylene glycol spacers and a lipid selected from the group consisting of a stearyl and a cholesterol. 
     
     
       19. The SNA of  claim 1 , wherein 30%-90% of the nucleotides in each of the oligonucleotides are modified. 
     
     
       20. The SNA of  claim 19 , wherein the modifications are 2-O-methyl modifications and phosphorothioate backbone modifications.